Objectives:: Our aim was to compare an AntiCD20 therapy (rituximab) for rheumatoid arthritis in two patient populations (Group 1), anti-TNFα naïve patients and inadequate responders to Anti-TNFα therapy (Group 2). Methods:: We analyzed the efficacy of the drug Rituximab (RTX) in RA patients who failed methotrexate (MTX) or had a relative or absolute contraindication to receive anti-TNFα therapy. Results:: 25 patients were identified according to the above criteria and followed up for a mean period of 6 months. Thirteen patients were biologic naïve and twelve patients had already failed anti-TNFα therapy. Group 1 used 2> DMARDs (32% vs 20%, p<0.005), group 2 had more years of disease progression (5±1.89 v s4.10±3.92, p<0.001). The remission as measured by the DAS28 reached faster in group 1 (1.25±0.12 vs 2.15±1.64, p<0,001). Severe infections especially by herpes viruses were more frequent in group 2. Conclusions:: Comparing clinical improvement in both groups the decrease of acute phase reactants and the clinical remission measured by DAS28 was reached in both groups, however it was reached more belatedly in group 2 (at 6 months), this is due to the fact that they have more years of the disease evolution and a higher HAQ.